The diverse central actions of serotonin (5-HT) are mediated by multiple recognition sites (5-HT1-3) receptors; 5-HT uptake sites). A growing body of evidence indicates that these sites play a key role in neuropsychopharmacology and are implicated in depression, anxiety, dementia and other disorders. The primary objective of our proposed research is the identification of radioligands for selective localization of 5-HT recognition sites in vivo in living human brain by single photon emission computed tomography (SPECT) or positron emission tomography (PET). Our target compounds are halogenated serotonergic ligands which may be labeled with I-125 for screening purposes, as well as with radionuclides appropriate for SPECT (1-123) and PET (C-11, F-18). The candidate ligands will be synthesized, characterized, and screened to define in vivo and in vitro binding profiles. The most promising ligands will be labelled with imaging radionuclides for SPECT or PET trials in baboon. Our work will provide ligands which are useful for in vitro, in vivo, autoradiographic and tomographic studies of cerebral 5-HT recognition sites. We recently found D-(+)-N1-ethyl-2-I-LSD (EIL) to display the highest specificity in vivo for 5-HT2 sites yet observed for any serotonergic ligand. We will focus immediate attention on (123I)-EIL for SPECT, and analogs of this compound labelled with C-11 or F-18 for PET. More exploratory work will be directed toward radioligands for 5-HT1A and 5-HT3 receptors as well as 5-HT uptake sites. Validation of imaging radioligands for 5-HT recognition sites in living brain lays the foundation for clinical studies, such as those we conducted with D-(+)-N1-((11/c)-methyl)-2-Br-LSD under this grant, and should have considerable positive impact upon studies of serotonergic function and dysfunction.